Project Summary The Tumor Biology Program aims to catalyze research within the ACC to advance understanding of the molecular mechanisms underlying cancer pathogenesis and to translate this knowledge to identify new and more effective preventive, diagnostic, prognostic and therapeutic approaches. This Program, which was founded in the early 1970s, continues to progressively respond to advances in cancer research. Its overarching scientific aims are to: 1) Elucidate the molecular and cellular basis of carcinogenesis, and 2) Translate these findings into durable clinical applications. To that end, the Program is organized around three central goals or themes: 1) Structural biology of molecules relevant to cancer, 2) The molecular and cellular basis of cancer, and 3) The use of model organisms to study cancer in vivo. Interactive, intra-Programmatic scientific affinity groups foster collaboration within and across themes, including: 1) Tthe tumor microenvironment, 2) RNA biology, 3) DNA repair and genomic stability, 4) Cancer cell metabolism (this spawned a new ACC Basic Science Center of Excellence), and 5) Organ-specific cancers, such as pancreatic (this has been integrated into the new ACC Pancreatic Translational Center of Excellence). The Program continues under the strong leadership of Anil Rustgi, MD, who fosters deep and impactful intra- and inter-Programmatic collaborative relationships. Program Leadership is also instrumental in recruiting new members (e.g., Drs. Berger, Feldser, Garcia, and Pur), mentoring junior faculty, establishing scientific affinity groups to leverage and further develop common research interests among faculty members, and organizing conferences and symposia. Program members are extremely actively involved in the training and mentorship of PhD students, MD/PhD students, and MD or PhD postdoctoral fellows by virtue of their leadership roles in the Penn Biomedical Graduate Studies, MD/PhD (MSTP) program and NIH T32 training grants. Program Leadership was highly successful in harnessing Institutional support to catalyze a tumor biology translational research initiative and increased translational research has been pursued in both thematic and organ-specific contexts. Its success is evident in the emergence of new transdisciplinary, disease-specific collaborations that join Program members with colleagues in Clinical Research and Population Science to study cancers, such as pancreatic and esophageal, in which there is an unmet need for improved diagnosis and treatment. Currently, the Program has 50 members from 16 departments and four different schools with total funding of $22M (annual direct costs) of which $18.7M is peer-reviewed and $5.6M is NCI-funded. Since 2010, members published 466 cancer-related papers, of which 15% were intra-Programmatic, 32% were inter-Programmatic, and 30% were multi-institutional.